Opioids like morphine, hydrocodone and oxycodone are generally the most effective therapeutic approach for treatment of moderate to severe pain. However, their use is limited by serious side effects, including rapid tolerance, constipation, respiratory depression, and high addictive potential. The frequency of clinical pain, coupled with a lack of alternative therapeutic options has led to a national health crisis centered on prescription opioid abuse. Alternative pain relievers with the analgesic potency of conventional opioids, but without their side effects and abuse potential are needed. The goal of this project is to develop and commercialize an alternative to conventional opioid analgesics with reduced side effects and without the addictive properties common to mu-opioid agonists. In our SBIR Phase I equivalent studies, N-naphthoyl-?- naltrexamine (NNTA) was shown to be orally and intravenously (i.v.) active and demonstrated potent analgesia without apparent addictive potential as indicated by lack of significant intrathecal tolerance, physical dependence, and abuse potential in standard rodent assays. We further showed that NNTA is highly selective for a novel biological target, the mu-kappa opioid heterodimer. We will now move NNTA through a series of IND-enabling studies targeting an initial indication of i.v. postoperative pain. We will first develop an FDA- compliant process for preparation of NNTA hydrochloride based on a previously demonstrated robust, three- step synthetic strategy. Upon completion of this milestone, we will obtain at least 30g of 95% NNTA using a scalable synthetic process. We will next perform studies to further differentiate NNTA from conventional opioids by identifying its potential to produce constipation and respiratory depression. Because NNTA targets the mu-kappa receptor and is not a mu agonist, we hypothesize that these side effects will be absent or greatly reduced compared to the effects produced by morphine. To explore its propensity to produce constipation, the effects of i.v. NNTA on gastric transit will be tested using the charcoal meal method and compared to the effects of i.v. morphine. We will then compare the effects of NNTA and morphine on respiration by using whole body plethysmography. In these studies we aim to show that NNTA produces less respiratory depression and less constipation than morphine at the ED50 of both compounds. Next, utilizing a CRO, we will advance NNTA through in vitro ADME, bacterial mutagenicity, and hERG assays. Additionally we will develop and validate bioanalytical methods exploring plasma PK properties in rodent and non-rodent species and validate analytical methods for compound formulation and vehicle stability. By advancing NNTA through these IND-enabling milestones, and further differentiating its side effect profile, this SBIR Phase II project prepares NNTA for planned SBIR Phase III studies that will advance it into Phase 1 human trials.